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PharmaTerra Inc. has staked a claim with its herbal remedy, ProBeta, which, if legitimate, could be the most profound treatment of diabetes to date.
According to a 1990 study published in the Journal of Ethnopharmacology, male albino rats demonstrated pancreatic regeneration when administered ProBeta. The study, conducted in Madras, India by researchers K. Radha Shanmugasundaram, PhD, E.R.B. Shanmugasundaram, PhD, and Amitava Dasgupta, PhD, supports a landmark discovery in which islet and beta cells were regenerated in an animal diabetes model.
"This is the first time in the literature that such an event has been reported," says Rolland Hebert, ND, chairman of PharmaTerra. "It has been thought that tissue regeneration in the pancreas cannot occur. Our team is the first to demonstrate that thinking as being incorrect. There is a residual capacity for regeneration."
Others in the diabetes community are saying that PharmaTerra's claims are not valid, and that the Journal of Ethnopharmacology is not a respected scientific journal.
"There is nothing wrong with alternative medicine-type practices as long as they perform double-blind, placebo-controlled trials looking at the effects of their products," says Bruce W. Bode, MD, of Atlanta Diabetes Associates.
ProBeta is PharmaTerra's first product. They purchased the research from the Indian scientists over one year ago. Prior to that, there was a bidding war for the research which PharmaTerra obtained for an undisclosed amount of money. They now assume all rights to the research, and employ the Indian research team as part of their staff.
ProBeta comes in a tablet form, consisting of 250 milligrams per tablet. In the eight years since the study on albino rats, PharmaTerra collaborated with the researchers who conducted the animal and subsequent human studies, and spent time further studying and refining the drug to make sure it was safe for distribution.
On the market since September 1998, ProBeta is a proprietary extract of Gymnema sylvestre that has demonstrated blood glucose regulation in clinical trials involving people with type 1 and 2 diabetes. Gymnema Sylvestre is an herb native to plants in central and southern India. The leaves of Gymnema sylvestre are the part of the plant that is used medicinally, however, the chemical components of the leaves which give it medicinal value have not yet been identified.
"ProBeta is a natural product that is the result of about 20 years of work," says Hebert.
According to the November 1998 issue of the American Journal of Natural Medicine, Gymnema sylvestre effectively lowers blood sugar in people with elevated levels. Some research indicates that it also decreases high cholesterol levels.
Albino Rats with Diabetes
PharmaTerra's study on male albino rats was just one study that has been conducted to test the effectiveness in lowering blood sugars. According to a 1983 issue of the Journal of Ethnopharmacology, studies were conducted on rabbits who had diabetes, and it was proven that Gymnema sylvestre helped regulate glucose metabolism. The experiment on albino rats, however, was the first to demonstrate that ProBeta not only helps regulate blood glucose levels in adult animal models with diabetes, but effectively helps regenerate islet and beta cells in the pancreas as well.
In the study on healthy, normoglycemic male albino rats, diabetes was induced using 55 milligrams of streptozotocin, which is a drug known to be toxic to the pancreas and beta cells. After destroying the pancreases of the albino rats, rendering them with only a few operational beta and islet cells, PharmaTerra theorized that any subsequent regeneration of the islet cells would have to be as a result of the administered Gymnema sylvestre extract.
"Streptozotocin-induced diabetes is not spontaneously reversible," says Hebert. "That is, once you use streptozotocin in these animals, they will never recover their ability to produce beta and islet cells on their own."
But according to Scott Robert King, president of Islet Sheet Medical in San Francisco, streptozotocin is not 100 percent reliable in killing all of the islet cells.
"You would have to run certain tests following the streptozotocin treatment to make sure the islets were dead," says King. "The regeneration of islets does occur, but it is a rare event. If the research showed that you had basically killed all of the islets and then a significant number of the rats then regained their function, that would be strong evidence that there was regeneration."
After streptozotocin-induced diabetes was established in the albino rat subjects, the scientists then established a group that would take ProBeta orally, and a control group that would not be treated with ProBeta. Fasting blood glucose levels were tested every five days, and within 60 days, rats taking ProBeta demonstrated normal fasting blood glucose levels.
Beta Cell Regeneration
When normal levels were achieved, researchers stopped giving the rats ProBeta, and kept them alive for 95 days. After 95 days, they were then killed, and their pancreatic tissue was removed for analysis. In conducting examinations of several parts of the rats' pancreatic tissue, the scientists made an overwhelming discovery. In the pancreatic tissue of the non-ProBeta-treated rats, there were still only a few islet and beta cells evident within the gastric region of the pancreas. On the other hand, the pancreatic tissue of the rats treated with ProBeta showed double the number of beta cells in the duodenal section of the pancreas than those rats who did not receive ProBeta.
"This was the first time it has been shown that you could double the number of beta and islet cells in an animal model of diabetes," says Hebert. "In the gastric, or stomach, section of the pancreas, where the streptozotocin kills most of the beta cells in the control animal group, there was about a 26-fold increase in the number of Islets of Langerhans, and about a 56-fold increase in the number of beta cells. That's going from almost no beta cells to substantial increases."
According to the same 1990 issue of the Journal of Ethnopharmacology, ProBeta was then administered to 27 human patients with type 1 diabetes in a three-year proof-of-concept experiment. Blood glucose levels and HbA1cs were compared to those measured in 37 control subjects who had diabetes and were being treated with insulin. After a month, patients treated with ProBeta began to develop mild hypoglycemic episodes. During the first six to eight months, HbA1c levels showed a significant reduction, and over the course of the study, all patients using ProBeta in the treatment group were able to reduce their insulin intake by nearly half. Mean blood glucose levels were reduced 32 percent, from 232 to 152 mg/dl.
ProBeta was also tested in 22 humans with type 2 diabetes, who were compared with a control group of 25 type 2s who used oral medication. Over the course of the 18 to 20-month study, patients treated with ProBeta were able to decrease their oral hypoglycemic medication doses by about one half, while HbA1cs were reduced 16-19 percent in the first 8 to 10 months, and 28-29 percent within 18 to 20 months. Additionally, five of the 22 patients were able to discontinue their conventional drug and maintain their blood glucose levels with ProBeta.
The researchers, however, could not determine whether there was beta cell regeneration in the human subjects who took ProBeta.
"That would require removing and dissecting the human pancreas, and I don't think any person would volunteer to do that," says Hebert.
Michael Baker, ND, vice president of clinical research at PharmaTerra, feels that the findings of the albino rat and human studies are extremely significant, and should be taken seriously.
"Essentially, what you are doing is giving people with diabetes a substance which is leading the body to start normalizing itself," says Baker. "The blood glucose levels become self-regulated more than before."
Baker says that the process of the body self-regulating its own blood glucose is a much healthier and safer alternative than taking insulin or oral antihyperglycemics.
"When you take insulin or oral antihyperglycemics, you're inducing extraneous self-regulation," says Baker. "Whenever you do that, it is not as good as the body regulating itself."
The Role of Stem Cells
According to PharmaTerra, there is no clear definition as to how ProBeta regenerates the pancreatic tissues of albino rats, but Hebert feels the answer resides in the role that stem cells play in the regenerative process. Stem cells, in individuals with diabetes, are the cells which line the ducts of the pancreas.
"We are uncertain as to how ProBeta acts upon the stem cells, but PharmaTerra is in the process of trying to find out the underlying molecular biology associated with pancreatic regeneration," say Hebert.
According to Aaron Vinik, MD, director of the Strelitz Diabetes Research Institute and vice chairman of the department of medicine at Eastern Virginia Medical School (EVMS), stem cells are precursor cells for pancreatic islets which, in all likelihood, reside in the ductular system.
"We can tell that one of those cells is destined to become an islet cell, and will transform from a ductile characteristic into a cell that makes insulin," says Vinik.
Vinik says that EVMS, along with the University of Wisconsin and the Johns Hopkins Institute, are the only places that have addressed the possibilities of taking stem cells and converting them into endocrine cells. According to Vinik, there are three conditions in which ductile cells can be coaxed into becoming islet cells.
* Cellophane Wrapping - This occurs when you wrap the ducts in cellophane, which produces partial obstruction of the ducts. New cells then grow out from the ducts, thus transforming into endocrine cells.
* Use of Ilotropin - Ilotropin is an extract of a regenerated pancreas which works by "turning on" insulin-producing cells in the pancreas.
* Islet Neogenesis Associated Peptide (INGAP) - This is a gene that was recently discovered that appears to be critical to the regeneration of islet cells. INGAP is an important protein in a very complicated cascade of proteins needed for islet regeneration. When Vinik's research team at EVMS injected the INGAP protein in streptozotocin-induced hamsters, the protein caused islet regeneration, and, essentially, cured the diabetes in 50 percent of the animals. The other 50 percent did not respond to the INGAP protein. EVMS and research partners at McGill University recently licensed the INGAP gene to Eli Lilly & Company.
PharmaTerra doctors recommend that patients with type 1 and 2 diabetes start at four capsules a day. When blood glucose has come down, doses can be reduced to two capsules. In human trials, no children under the age of 10 were administered ProBeta, so PharmaTerra does not have a recommended dosage for such individuals.
Between six weeks to two months, Hebert says, people with type 2 diabetes will begin to see results. For those with type 1 diabetes, the effects will be seen between three and six months.
"People with type 2 diabetes respond more quickly to using ProBeta because they already have beta cells that are functioning somewhat," says Hebert. "They have a beta cell mass that is not zero, while the type 1 individual has a beta cell mass that approaches zero."
The Hatch Act
Because ProBeta is a natural product, and is being introduced in the United States as a supplement, it falls under what is known as the Hatch Act or the Dietary Supplement Health and Education (DSHEA) laws for nutritional supplements. These laws govern what can and cannot be marketed as supplements in the United States, as well as what claims may or may not be made. Under the Hatch Act, as long as a company does not claim its supplement cures a disease, the only premarket requirement is that the company have scientific proof that the product is safe. According to FDA laws, PharmaTerra can only say that ProBeta helps maintain healthy glucose levels and healthy pancreatic function. Some individuals, however, feel that ProBeta is on the supplemental market for a reason.
"Whatever evidence PharmaTerra has that points to islet and beta cell regeneration has either not been submitted to the FDA for approval, or the FDA did not believe it was adequate," says Varro Tyler, PhD, ScD, retired professor of pharmacology at Purdue University, and author of the books "Herbs of Choice" and "The Honest Herbal."
Tyler feels that ProBeta might indeed facilitate the regeneration of islet and beta cells, but he calls the Journal of Ethnopharmacology an insignificant clinical journal.
Reaction in the Diabetes Community
Despite ProBeta being marketed as a supplemental diabetes medication, several people in the diabetes community would try anything that has medicinal qualities pertaining to beta and islet cell regeneration.
"I would try any medication that could possibly help me lead a more productive life," says Richard H. Velten, who has had diabetes for 22 years. "I have tried Gymnema extracts in the past, and I did not find that it had any noticeable effects on my blood sugars. If this product [ProBeta] does what it claims to do, I would be receptive to trying it."
Mary Mullusky of Staten Island, New York, has type 2 diabetes, and believes in alternative medication. Mullusky says she would take seriously any claim that a drug regenerates beta and islet cells in the pancreas of an animal diabetes model.
"More research needs to be done, I'm sure, but I would definitely try such a product," says Mullusky.
David Chasey of Pittsburgh, Pennsylvania, feels that herbal remedies have centuries, if not millenniums, of solid reputation behind them, which amount to solid anecdotal evidence. Although he would like to see more testing on ProBeta, he would consider trying it to control his diabetes.
"What is hailed as scientific testing often doesn't mean much, but I would try any product that demonstrated islet and beta cell regeneration in an animal diabetes model," says Chasey.
Others, however, have their misgivings about a non-FDA-approved drug that has been scientifically proven to regenerate islet and beta cells in an albino rat.
"I would wait for some research from some medical facility not involved in selling or advertising this product," says Sharon D'Nelly-Warady of Sunnyvale, California.
Some physicians and diabetes educators feel that pancreatic regeneration that occurs in albino rats when administered a drug would not hold true for humans.
"If it's too good to be true, then it probably is," says Keith Campbell, CDE, professor of pharmacy at Washington State University. "Regeneration of tissues is a very complicated process, and the ability to do it in various animal species varies greatly from one to another, particularly humans. "
Campbell stresses the necessity of a double-blind study, in which an independent agency, researchers and animal handlers were blinded to what is in a product when testing it.
"If a double-blind study did not occur, then this is not a legitimate study," says Campbell, who also feel that much more research needs to be conducted on things such as determining the toxicity of the Gymnema plant, as well as conducting safety studies to determine whether other organs are impaired while pancreatic regeneration occurs.
PharmaTerra says that the study was not reported in the literature as being a double-blind study, but was a standard controlled study using an animal model of diabetes. Furthermore, PharmaTerra emphasizes that ProBeta was put through the same test in the animals that you would normally expect the FDA to require. Everything was done in animals before it went into humans.
"There were no side effects with taking ProBeta in either the animal or human subjects," says Hebert. "We wouldn't put something onto the marketplace if it had deleterious side effects or affected other organs in the body."
One endocrinologist, speaking on the condition of anonymity, feels that neither ProBeta or PharmaTerra is legitimate.
"It sounds like a bunch of hogwash," says the endocrinologist. "If it were legitimate, these studies would have been conducted by legitimate laboratories using animals other than albino rats. When you have a legitimate product, you have it done with a recognized research group."
Campbell feels that many herbal drugs are on the supplemental market because they are not legitimate.
"If this product is legitimate, and it does in humans what they're claiming it does in albino rats, they [PharmaTerra] can make hundreds of billions of dollars," says Campbell.
Michael Baker of PharmaTerra agrees that his company's research findings might be hard to swallow, and understands that nay-sayers in the diabetes community are always going to have their apprehensions about herbal remedies that treat diabetes.
"Endocrinologists are going to say that it's impossible for ProBeta to do to humans what it did to albino rats because they [endocrinologists] don't believe that a pancreas is able to regenerate," says Baker. "We would like to think of science as being an open-minded construct, but that just isn't the case. The endocrinologists are certainly going to have a hard time believing that some plant extract can do this."
ProBeta is not inexpensive, running at about $68 per bottle. Each bottle contains 120 pills. According to Hebert, however, any benefits that a patient might derive from ProBeta, as far as lowering blood glucose and regenerating beta cells, is nothing less than progressive.
"If you can give somebody with diabetes a drug that would increase beta cell mass, and have the autoimmune destructive aspect of the immune system under control, in theory, that is a viable alternative to any other approach of treating diabetes," says Hebert. "Nobody is pursuing that right now because the approach is too novel."
Jan 1, 1999